Lymphatic vessel valves require RASA1 for development and function

Ras GTPase activating proteins (RasGAPs) control the activation of Ras, a small GTP-binding protein that regulates signal transduction pathways involved in cell growth, survival, and differentiation. Inactivating mutations the RasGAP RASA1 cause a blood and lymphatic vessel (LV) disorder known as capillary malformation-arteriovenous malformation, though exactly how loss of RASA1 function contributes to LV leakage is unclear.

This week in the JCI, research led by Philip King at University of Michigan Medical School reports that LV development and function critically depends on RASA1 activity. Ablation of RASA1 in adult mice led to specific defects in lymphatic valves that impaired the efficiency of LV pumping. Valve closure tests revealed that RASA1-deficient lymphatic vessels failed to prevent back-leak across valves. Moreover, ablating RASA1 in embryos impaired LV valve development. Together, these findings support an essential role for RASA1 in both LV formation and maintenance.

The accompanying video visualizes LV responses to increases in downstream pressure. In the top panel, as pressure increases, LV valves in wildtype mice rapidly close to prevent backflow. In the bottom panel, valve failure in RASA1-deficient mice results in backflow into the upstream regions of the LV.

Abstract

Capillary malformation–arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) disorder that is caused by inherited inactivating mutations of the RASA1 gene, which encodes p120 RasGAP (RASA1), a negative regulator of the Ras small GTP-binding protein. How RASA1 mutations lead to the LV leakage defects that occur in CM-AVM is not understood. Here, we report that disruption of the Rasa1 gene in adult mice resulted in loss of LV endothelial cells (LECs) specifically from the leaflets of intraluminal valves in collecting LVs. As a result, valves were unable to prevent fluid backflow and the vessels were ineffective pumps. Furthermore, disruption of Rasa1 in midgestation resulted in LEC apoptosis in developing LV valves and consequently failed LV valvulogenesis. Similar phenotypes were observed in induced RASA1-deficient adult mice and embryos expressing a catalytically inactive RASA1R780Q mutation. Thus, RASA1 catalytic activity is essential for the function and development of LV valves. These data provide a partial explanation for LV leakage defects and potentially other LV abnormalities observed in CM-AVM.